Elevated expression of the multifunctional cytokine transforming growth factor β1 (TGF-β1) is causatively linked to kidney fibrosis progression initiated by diabetic, hypertensive, obstructive, ischemic and toxin-induced injury. Therapeutically relevant approaches to directly target the TGF-β1 pathway (e.g., neutralizing antibodies against TGF-β1), however, remain elusive in humans. TGF-β1 signaling is subjected to extensive negative control at the level of TGF-β1 receptor, SMAD2/3 activation, complex assembly and promoter engagement due to its critical role in tissue homeostasis and numerous pathologies. Progressive kidney injury is accompanied by the deregulation (loss or gain of expression) of several negative regulators of the TGF-β1 signaling cascade by mechanisms involving protein and mRNA stability or epigenetic silencing, further amplifying TGF-β1/SMAD3 signaling and fibrosis. Expression of bone morphogenetic proteins 6 and 7 (BMP6/7), SMAD7, Sloan–Kettering Institute proto-oncogene (Ski) and Ski-related novel gene (SnoN), phosphate tensin homolog on chromosome 10 (PTEN), protein phosphatase magnesium/manganese dependent 1A (PPM1A) and Klotho are dramatically decreased in various nephropathies in animals and humans albeit with different kinetics while the expression of Smurf1/2 E3 ligases are increased. Such deregulations frequently initiate maladaptive renal repair including renal epithelial cell dedifferentiation and growth arrest, fibrotic factor (connective tissue growth factor (CTGF/CCN2), plasminogen activator inhibitor type-1 (PAI-1), TGF-β1) synthesis/secretion, fibroproliferative responses and inflammation. This review addresses how loss of these negative regulators of TGF-β1 pathway exacerbates renal lesion formation and discusses the therapeutic value in restoring the expression of these molecules in ameliorating fibrosis, thus, presenting novel approaches to suppress TGF-β1 hyperactivation during chronic kidney disease (CKD) progression.

The clear cell variant of renal cell carcinoma (ccRCC) is the most common renal epithelial malignancy and responsible for most of the deaths from kidney cancer. Patients carrying inactivating mutations in the Von Hippel-Lindau (VHL) gene have an increased proclivity to develop several types of tumors including ccRCC. Normally, the Hypoxia Inducible Factor alpha (HIF-α) subunits of the HIF heterodimeric transcription factor complex are regulated by oxygen-dependent prolyl-hydroxylation, VHL-mediated ubiquitination and proteasomal degradation. Loss of pVHL function results in elevated levels of HIF-α due to increased stability, leading to RCC progression. While HIF-1α acts as a tumor suppressor, HIF-2α promotes oncogenic potential by driving tumor progression and metastasis through activation of hypoxia-sensitive signaling pathways and overexpression of HIF-2α target genes. One strategy to suppress ccRCC aggressiveness is directed at inhibition of HIF-2α and the associated molecular pathways leading to cell proliferation, angiogenesis, and metastasis. Indeed, clinical and pre-clinical data demonstrated the effectiveness of HIF-2α targeted therapy in attenuating ccRCC progression. This review focuses on the signaling pathways and the involved genes (cyclin D, c-Myc, VEGF-a, EGFR, TGF-α, GLUT-1) that confer oncogenic potential downstream of the VHL-HIF-2α signaling axis in ccRCC. Discussed as well are current treatment options (including receptor tyrosine kinase inhibitors such as sunitinib), the medical challenges (high prevalence of metastasis at the time of diagnosis, refractory nature of advanced disease to current treatment options), scientific challenges and future directions.

Cancer-associated fibroblasts (CAFs) are a heterogenous population of stromal cells found in solid malignancies that coexist with the growing tumor mass and other immune/nonimmune cellular elements. In certain neoplasms (e.g., desmoplastic tumors), CAFs are the prominent mesenchymal cell type in the tumor microenvironment, where their presence and abundance signal a poor prognosis in multiple cancers. CAFs play a major role in the progression of various malignancies by remodeling the supporting stromal matrix into a dense, fibrotic structure while secreting factors that lead to the acquisition of cancer stem-like characteristics and promoting tumor cell survival, reduced sensitivity to chemotherapeutics, aggressive growth and metastasis. Tumors with high stromal fibrotic signatures are more likely to be associated with drug resistance and eventual relapse. Clarifying the molecular basis for such multidirectional crosstalk among the various normal and neoplastic cell types present in the tumor microenvironment may yield novel targets and new opportunities for therapeutic intervention. This review highlights the most recent concepts regarding the complexity of CAF biology including CAF heterogeneity, functionality in drug resistance, contribution to a progressively fibrotic tumor stroma, the involved signaling pathways and the participating genes.

Although yes‐associated protein (YAP) and transcriptional coactivator with PDZ‐binding motif (TAZ), nuclear transducers of the Hippo pathway, are mostly silent in adult organs, aberrant activation of YAP/TAZ promotes tumorigenesis and abnormal tissue repair. The extent of involvement of TAZ in chronic kidney disease (CKD) is unknown. In our study, increased TAZ nuclear accumulation and expression in the tubulointerstitium was readily evident in 3 models of renal injury including obstructive, aristolochic acid (AA), and diabetic nephropathy, correlating with fibrosis progression. Stable TAZ overexpression in human kidney (HK)‐2 epithelial cells promoted connective tissue growth factor (CTGF), fibronectin, vimentin, and p21 expression, epithelial dedifferentiation, and growth inhibition, in part, via Sma mothers against decapentaplegic homologue (SMAD)‐3‐dependent CTGF induction. CTGF secretion by TAZ‐overexpressing epithelium also triggered proliferative defects in nonengineered HK‐2 cells confirming a nonautonomous role of TAZ (via a paracrine mechanism) in orchestrating kidney epithelial cell‐cell communication. Renal tubular‐specific induction of TGF‐β1 in mice and TGF‐β1 stimulation of HK‐2 cells resulted in TAZ protein up‐regulation. TAZ stable silencing in HK‐2 cells abrogated TGF‐β1–induced expression of target genes without affecting SMAD3 phosphorylation, which is also crucial for fibrotic reprogramming. Thus, TAZ was activated in fibrosis through TGF‐β1–dependent mechanisms and sustained TAZ signaling promotes epithelial maladaptive repair. TAZ is also a novel non‐SMAD downstream effector of renal TGF‐β1 signaling, establishing TAZ as a new antifibrosis target for treatment of CKD.—Anorga, S., Overstreet, J. M., Falke, L. L., Tang, J., Goldschmeding, R. G., Higgins, P. J., Samarakoon, R. Deregulation of Hippo‐TAZ pathway during renal injury confers a fibrotic maladaptive phenotype. FASEB J. 32, 2644–2657 (2018). www.fasebj.org

Rac‐GTPases are major regulators of cytoskeletal remodeling and their deregulation contributes to numerous pathologies. Whether or how Rac promotes tubulointerstitial fibrosis and chronic kidney disease (CKD) is currently unknown. We showed that the major profibrotic cytokine, TGF‐β1 promoted rapid Rac1‐GTP loading in human kidney 2 (HK‐2) human renal epithelial cells. A Rac‐specific chemical inhibitor, EHT 1864, blocked TGF‐β1‐induced fibrotic reprogramming in kidney epithelial cells and fibroblasts. Stable Rac1 depletion in HK‐2 cells, moreover, eliminated TGF‐β1‐mediated non‐SMAD pathway activation [ e.g ., Src, epidermal growth factor receptor (EGFR), p53] and subsequent plasminogen activator inhibitor‐1 (PAI‐1), connective tissue growth factor, fibronectin, and p21 induction. Rac1 and p22 ^phox knockdown abrogated free radical generation by TGF‐β1 in HK‐2 cells, consistent with the role of Rac1 in NAPD(H). TGF‐β1‐induced renal epithelial cytostasis was also completely bypassed by Rac1, p22 ^phox , p47 ^phox , and PAI‐1 silencing. Rac1b isoform expression was robustly induced in the fibrotic kidneys of mice and humans. Intraperitoneal administration of EHT 1864 in mice dramatically attenuated ureteral unilateral obstruction‐driven EGFR, p53, Rac1b, yes‐associated protein/transcriptional coactivator with PDZ‐binding motif activation/expression, dedifferentiation, cell cycle arrest, and renal fibrogenesis evident in vehicle‐treated obstructed kidneys. Thus, the Rac1‐directed redox response is critical for TGF‐β1‐driven epithelial dysfunction orchestrated, in part, via PAI‐1 up‐regulation. Rac pathway inhibition suppressed renal oxidative stress and maladaptive repair, identifying Rac as a novel therapeutic target against progressive CKD.—Patel, S., Tang, J., Overstreet, J. M., Anorga, S., Lian, F., Arnouk, A., Goldschmeding, R., Higgins, P. J., Samarakoon, R. Rac‐GTPase promotes fibrotic TGF‐β1 signaling and chronic kidney disease via EGFR, p53, and Hippo/YAP/TAZ pathways. FASEB J. 33, 9797–9810 (2019). www.fasebj.org